Biomedical subjects
Publications and source records attributed to T Unger.
A modification of the Bratton-Marshall reaction for the quantitative determination of enzymically released p-nitroaniline is described. It is very sensitive, easily performed, shows good reproducibility, and it is suitable for routine use in clinical chemistry.
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The novel technique of microdialysis has been used to examine the basal and K+-induced release of catecholamines and metabolites from the anterior hypothalamus of the urethane-anaesthetized rat in vivo. A high pressure liquid chromatographic assay was developed to simultaneously measure endogenous noradrenaline, dopamine and their intraneuronal metabolites 3,4-dihydroxyphenylglycol (DOPEG) and 3,4-dihydroxyphenylacetic acid (DOPAC) respectively, in each 60 microliters dialysate sample. The effect of replacing Ca2+ in the perfusion fluid with a low concentration of Cd2+, which blocks Ca2+ effects, was also studied. Increasing the K+ concentration in the perfusion fluid elicited a concentration-dependent increase in noradrenaline and dopamine release. In contrast, there were marked reductions in DOPEG and DOPAC which were not concentration-dependent. In the Ca2+-depleted conditions, the K+-induced increase in amine release was significantly attenuated, but the reductions in the metabolites were not affected. We suggest that the mechanisms contributing to the observed reductions in the metabolites may be inhibition of neuronal reuptake, an increase in neuronal efflux, an enhancement of vesicular uptake and a decrease in vesicular efflux.
From pharmacological investigations and clinical studies, it is known that angiotensin converting enzyme (ACE) inhibitors exhibit additional local actions, which are not related to hemodynamic changes and which cannot be explained only by interference with the renin angiotensin system (RAS) by means of an inhibition of angiotensin II (ANG II) formation. Since ACE is identical to kininase II, which inactivates the nonapeptide bradykinin (BK) and related kinins, potentiation of kinins might be responsible for these additional effects of ACE inhibitors. a) In rats made hypertensive by aortic banding, the effect of ramipril in left ventricular hypertrophy (LVH) was investigated. Ramipril in the antihypertensive dose of 1 mg/kg/day for 6 weeks prevented the increase in blood pressure and the development of LVH. The low dose of ramipril (10 micrograms/kg/day for 6 weeks) had no effect on the increase in blood pressure or on plasma ACE activity but also prevented LVH after aortic banding. The antihypertrophic effect of the higher and lower doses of ramipril, as well as the antihypertensive action of the higher dose of ramipril, was abolished by coadministration of the kinin receptor antagonist icatibant. In the regression study the antihypertrophic actions of ramipril were not blocked by the kinin receptor antagonist. Chronic administration of BK had similar beneficial effects in a prevention study which were abolished by icatibant and NG-nitro-L-arginine (L-NNA). In a one year study the high and low dose of ramipril prevented LVH and fibrosis. Ramipril had an early direct effect in hypertensive rats on the mRNA expression for myocardial collagen I and III, unrelated to its blood pressure lowering effect.(ABSTRACT TRUNCATED AT 250 WORDS)
The activity and products of cellular oncogenes can be altered by various processes, such as the nearby integration of a retroviral genome, point mutation within the oncogene coding region, gene amplification, and chromosomal translocation (reviewed in ref. 1). Our work has provided an example of oncogene activation by yet a different process; the integration of an endogenous retrovirus-like DNA element (identified as an intracisternal A particle or IAP genome) within the coding region of the oncogene c-mos in a mouse plasmacytoma, XRPC 24. The rearranged c-mos gene of XRPC24 is actively transcribed and has transforming activity, suggesting some role for activated c-mos in the progression of the XRPC24 tumour. In this report we describe rearrangement of c-mos in a second mouse plasmacytoma, NSI, and in two hybridomas. In this case, as in XRPC24, c-mos was split by the insertion of a IAP genome. The rearranged c-mos genes (rc-mos) of NSI and XRPC24 differ in three major aspects: (1) The site of IAP integration in c-mos is in codon 30 in NSI but in codon 88 in XRPC24; (2) The orientation of the integrated IAP relative to c-mos is 'tail-to-head' in NSI and 'head-to-head' in XRPC24; and (3) transcriptional activity of rc-mos in NSI is much lower than in XRPC24. The two latter points suggest a correlation between the orientation of the long terminal repeat (LTR) of IAP relative to c-mos and its activity upon IAP integration.
The cardiocytes of mammalian cardiac atria contain granules very similar to those in endocrine cells. The number of these atrial granules is related directly to salt loading and blood volume. Furthermore, crude extracts of rat atria and granule preparations have powerful natriuretic and diuretic effects. These effects are mediated by peptides identified previously as atrial natriuretic factor (ANF). The peptides are derived from a common precursor, whose structure has been elucidated recently. Although there is indirect evidence from morphological studies that at least some of these peptides may be released into the blood and function as hormones, their presence in the blood has not yet been demonstrated. Here we describe a sensitive and specific radioimmunoassay for ANF and its stimulation on volume loading.
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The mechanism of antihypertensive action of converting enzyme (CE) inhibitors was studied by comparing two compounds of different potency. Spontaneously hypertensive rats (SHRSP) were treated orally with the CE inhibitors Hoe498 and MK421 for periods of 2 and 4 weeks. The threshold antihypertensive dose of Hoe498 was below 0.1 mg/kg/day, and of MK421 1 mg/kg/day. Blood pressure was normalized with 10 mg/kg/day Hoe498 and 30 mg/kg/day MK421. The reduction of the pressor responses to intravenous angiotensin I (ANG I), the potentiation of the bradykinin depressor responses, and the decreases of plasma angiotensin II levels or urinary aldosterone excretion were nor correlated to the antihypertensive potency of the drugs. However, following equi-dose treatment (10 mg/kg/day) with both compounds inhibition of tissue CE activity in the vascular wall of the aorta, in the lung, the kidney, and the brain cortex was more marked with Hoe498 than with MK421. Hoe498 also reduced CE activity in the heart, and adrenal gland, and in other brain areas, and attenuated the pressor responses to intracerebroventricularly injected ANG I. Our results provide the first direct evidence for tissue CE inhibition following chronic oral CE inhibitor treatment, and support the contention that inhibition of the enzyme in target organs such as vascular wall, kidney, heart, or brain may be involved in the antihypertensive action of these drugs.
Inhibition of angiotensin II generation in the plasma does not fully explain the antihypertensive effects of converting enzyme (CE) inhibitors. Thus, we investigated the role of CE inhibition in the tissue for the antihypertensive action of these drugs. After discontinuation of 4 weeks of oral treatment with either Hoe498 (3 mg/kg/day) or MK421 (30 mg/kg/day) in spontaneously hypertensive rats (SHRSP), the reduced pressor response to intravenous angiotensin I was normalized within 1 day, although systolic and diastolic blood pressure remained decreased during a 1 week post-treatment follow-up period. Two weeks of oral treatment with Hoe498 (1 mg/kg/day) and MK421 (30 mg/kg/day) in SHRSP lowered blood pressure markedly and inhibited CE in the plasma (43% and 22%), lung (85% and 33%), kidney (76% and 76%), aortic wall (75% and 48%), and (with Hoe498) in the heart (55%). After drug discontinuation, blood pressure remained decreased for an additional 2 weeks, whereas plasma CE was normal or elevated during the follow-up period. However, tissue CE activity measured 1 week after drug withdrawal was still inhibited in the aortic wall (67% and 30%) and in the kidney (48% and 41%). These results support the hypothesis that the prolonged antihypertensive action of CE inhibitors may be related to persistent CE inhibition in tissues such as vascular wall and kidney. Further, the data support the importance of CE inhibition at target sites other than plasma and lung vascular endothelium.
The novel prodrug-converting-enzyme (CE) inhibitor perindopril (S9490-3) diacid was found to be as potent as ramipril (Hoe498) diacid and more potent than enalapril (MK421) diacid and captopril against rat plasma CE in vitro (IC50 values were 3 X 10(-9), 2 X 10(-9), 1 X 10(-8), and 6 X 10(-8) mol/L, respectively). Four-week oral treatment with perindopril (0.1, 1, 3, and 10 mg/kg/day) in spontaneously hypertensive rats (SHRSP) lowered blood pressure (BP) dose-dependently with a threshold dose of 0.1 mg/kg/day and normalization of BP following doses between 1-3 mg/kg/day. Plasma CE was inhibited, angiogensinogen lowered, plasma renin concentration (PRC) and angiotensin I (ANGI) increased, all dose-dependently. CE was also inhibited in kidney, aortic wall, heart, lung, hypophysis, and brain cortex. Upon drug withdrawal, the BP depressant effect outlasted the effects on the plasma renin-angiotensin system (RAS) by more than a week. Perindopril, ramipril (both 1 mg/kg/day), and enalapril (30 mg/kg/day) showed equal antihypertensive actions in SHRSP, although their effects on parameters of the RAS in plasma were different. Our data reveal perindopril to be a potent antihypertensive drug. The findings are consistent with the view that the antihypertensive actions of CE inhibitors cannot be directly related to inhibition of the RAS in the plasma. Local interference with the RAS in tissue appears to be an additional factor involved.
The objective of this study was to compare the antihypertensive efficacy and safety of losartan and mibefradil. 324 outpatients (57 +/- 9.2 years) with mild to moderate hypertension were randomly allocated in a double-blind fashion to receive 50 mg of losartan or mibefradil once daily p.o. for 6 weeks after 2 weeks of placebo run-in. Titration was then forced to 100 mg of losartan or mibefradil for an additional 6 weeks. Patients were assessed at baseline, 6 and 12 weeks. The primary efficacy variable was change in predose sitting diastolic (SDBP) and systolic (SSBP) blood pressure at 12 weeks. Secondary variables included change in mean 24-hour ambulatory blood pressure and comparison of safety and tolerability. Both treatments lowered SSBP and SDBP at 6 and 12 weeks (week 6: mibefradil -14/-9 mm Hg; losartan -12/-7 mm Hg) (P <0.001). The primary objective, a difference between treatments in reduction of SSBP and SDBP at week 12 could be demonstrated (mibefradil -22/-16 mm Hg; losartan -16/-10 mm Hg) (P=0.003 and P=0.001, respectively). Twenty-four-hour SBP and 24-hour DBP were reduced (P<0.001) within each treatment group at weeks 6 and 12. The secondary objective, a difference between treatments in reduction of 24-hour blood pressure at week 12 could be demonstrated (P<0.001). Twenty-four-hour heart rate was lowered in the mibefradil group at weeks 6 and 12 (P < 0.001). Responder rates at 6 and 12 weeks were 56.2% and 78.5% for mibefradil versus 56.1% and 55.3% for losartan (P = 0.001). Both treatments were equally well tolerated. This study demonstrates that 50 mg losartan is comparably effective to 50 mg mibefradil in the treatment of mild to moderate hypertension with 100 mg mibefradil being more potent than losartan.
We have developed a new method for urine collection in conscious, unrestrained rats through a chronic indwelling ureteral catheter, which allows direct differential sampling of small urine fractions over periods as small as 1 min. The technique was validated in intact and unilaterally nephrectomized rats by cumulative intravenous saline loading. Comparison of kidney with ureter catheter and contralateral kidney (urine collection from the bladder) revealed no differences in glomerular filtration rate and urine production between both kidneys. One week after catheter implantation in unilaterally nephrectomized rats, signs of renal functional disturbance as assessed by glomerular filtration rate, urine concentrating capacity after 24 h water deprivation, and plasma and urinary urea concentrations before and after water deprivation were not detected. Our technique provides a novel tool for direct measurements of short-term changes in urine composition in conscious animals.
Recurrent and advanced cancer in the head and neck region is usually associated with limited therapeutic concepts and a dismal prognosis. Efforts mainly focus on palliative treatment in order to improve the patient's quality of life. From May 1989 to December 1994, a total of 120 intra-operative radiotherapy (IORT) procedures with high-energy electron beams (mean energy: 7 MeV: mean dose: 20 Gy) were performed in 95 patients. Therapy was usually performed under endotracheal anaesthesia (84%). There were 91 cases (75.8%) of recurrence in the lymph nodes of the neck and 14 cases (11.7%) of local recurrence. 15 patients (12.5%) received IORT as part of the initial treatment. Considering the palliative nature of IORT in these patients, only an R2 resection (gross residual tumour) was achieved in 71.7%. Local tumour control was nonetheless possible in 17% (R2 resection) to 64% (complete R0 resection), with a mean 11-month follow-up period for survivors (mean for deceased patients: 8 months). Regarding palliative criteria, IORT proved to be feasible since patients profited from short hospitalisation (median: 10 days), a low complication rate (27 instances; e.g. tracheostomy: 11; necrosis: 8, or fistula: 3) and, in part, a substantial reduction of pain (73.8%). Most of them regained physical and psychic integrity for weeks to months and were able to take part in social life during the final stage of their disease.
The cardiovascular effects of opioid peptides have been studied. Leucine-enkephalin (Leu-ENK) produced blood pressure (BP) increases following administration into the lateral brain ventricles (i.v.t.), into the cisterna magna (i.c.i.), and following intravenous (i.v.) administration. Heart rate (HR) increases were observed following all routes of administration (threshold for BP and HR effects at 0.3 nmole, maximum at 360 nmoles). The cardiovascular effects were independent of generalized seizures, which may occur at higher doses of enkephalins (ENK). D-alanine-enkephalin (D-Ala-ENK) attenuated the vagal component of the baroreceptor reflex in cats. This was indicated by the findings that HR did not decrease following D-Ala-ENK-induced BP increases and that the compensatory decreases in HR following i.v. pressor doses of angiotensin II (ANG II) were markedly attenuated in cats treated with i.v.t. D-Ala-ENK. Naloxone inhibited the BP and HR effects following i.c.i. and i.v., but not following i.v.t., administration of Leu-ENK. The i.v.t. Leu-ENK effect were inhibited by beta-adrenergic receptor blockade. Bratteboro rats homozygous for hereditary diabetes insipidus with total absence of antidiuretic hormone (ADH) synthesis responded with BP decreases following i.v.t. Leu-ENK, while BP increases were observed in control Long-Evans rats. Blood pressure increases to i.v.t. Leu-ENK were markedly greater in spontaneously hypertensive rats of the stroke-prone strain (SHR-sp) than in normotensive control rats; SHR-sp exhibit a humoral pattern of increased ADH, ACTH, and catecholamines, presumably due to central peptidergic stimulation. The known effects of opioid peptides on these hormones and the observed cardiovascular responses suggest a possible participation of this peptide system in the maintenance of high BP in the SHR-sp.
Effects of intracerebroventricular (i.c.v) injection of [D-Ala2]-methionine-enkephalinamide (DAME) on blood pressure (BP), heart rate, and baroreceptor reflex sensitivity were studied in conscious cats. DAME was administered at doses between 5 and 100 nmoles. Blood pressure and heart rate increased dose dependently. The sensitivity of the baroreceptor reflex was attenuated for 15 to 60 minutes after DAME administration; this was independent of the BP changes. The effects of enkephalin on BP and baroreceptor reflex were abolished by i.c.v. naloxone. DAME caused pathological changes in the electroencephalogram (EEG) characterized by sharp waves in the hippocampus recordings and a loss of theta activity in the electrocorticogram. Behavioral changes were characterized by decreased physical mobility and anxiousness. These behavioral and EEG changes lasted for a longer period of time than the cardiovascular changes; they were also counteracted by naloxone. It is concluded that DAME produces a centrally mediated vasopressor response and a baroreceptor reflex attenuation and that, with respect to the time course, the effects on the baroreceptor reflex are separated from those on BP behavior and EEG, but not on heart rate. The fact that all effects of enkephalin on the parameters tested in the present experiment were completely antagonized by naloxone suggests that they are mediated by naloxone-sensitive enkephalin brain receptors.
The aim of the present study was to investigate whether the presence of arginine vasopressin (AVP) is necessary for the establishment of high blood pressure in spontaneously hypertensive rats (SHR). For this purpose we crossbred SHR of the stroke-prone substrain (SHRSP) with rats homozygous for hypothalamic diabetes insipidus of the Brattleboro strain (DI) which are unable to synthetize AVP. The successful introduction of the DI gene into the SHRSP strain (SHRDI) was demonstrated by the following observations: In 10-month-old rats, water intake was similarly elevated in SHRDI as in DI rats (137 +/- 6.5 vs 125 +/- 10.5 ml per 24 hours). AVP was undetectable in the plasma, in the hypothalamus, and in the pituitary of SHRDI and DI rats. Urine osmolality and urinary concentration of sodium and potassium were markedly reduced. SHRDI and DI did not adequately concentrate their urine during an 8-hour period of water deprivation, but both strains of rats responded well with a fall in urine output and a rise in urine osmolality to subcutaneous administration of the non-pressor analog of AVP, DDAVP. Mean arterial blood pressure was markedly increased in SHRDI as well as in SHRSP (184 +/- 9.7 vs 197 +/- 5.2 mm Hg). Thus, we have developed a new line of spontaneously hypertensive rats homozygous for hypothalamic diabetes insipidus. From this finding it is concluded that AVP is not essential for the development and maintenance of spontaneous hypertension of rats.